N-substituted trifluoromethylphenyltetrahydropyridines, process for the preparation thereof, intermediates in said process and pharmaceutical compositions containing them

ABSTRACT

A method is disclosed for the treatment of neuronal degenerative processes. The method comprises administering 1-[4-(3-trifluoromethylphenyl)-1, 2, 3, 6-tetrahydropyrid-1-yl]-2-)6, 7-dimethoxynaphth-2-yl)ethane or a pharmaceutically acceptable salt thereof to a mammal suffering from a neuronal degenerative process.

This application is a continuation-in-part of application Ser. No.08/141,066, filed Oct. 26, 1993, now U.S. Pat. No. 5,462,945, issuedOct. 31, 1995, which is a continuation of application Ser. No.07/705,704, filed May 23, 1991, now U.S. Pat. No. 5,281,606, issued Jan.25, 1991.

The present invention concerns new N-substituted4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines useful in thetreatment of intestinal motility disorders.

More particularly, the present invention refers to new compounds of thefollowing general formula ##STR1## wherein A represents a group --E--Gor --L--M, where

--E-- is a straight or branched alkylene radical of from 2 to 4 carbonatoms,

--G represents a radical selected from the group consisting of naphthylmono-substituted with hydroxy or (C₁ -C₄)alkoxy: naphthyl di-substitutedwith hydroxy, (C₁ -C₄)alkoxy or (C₁ -C₄)alkyl; or naphthyl substitutedwith methylenedioxy,

--L-- is a --Q--CH(OH)-- group wherein --Q-- is a straight or branchedalkylene radical of from 1 to 3 carbon atoms, and

--M represents a radical selected from the group consisting of naphthyl;naphthyl mono- or di-substituted with hydroxy, (C₁ -C₄)alkoxy or (C₁-C₄)alkyl or naphthyl substituted with methylenedioxy; pyridyl; or (C₁-C₄)alkyl-pyridyl,

and their salts with mineral or organic acids.

GB-A-881894 describes 1-aroylalkyl-4-aryl-1,2,3,6-tetrahydropyridines offormula ##STR2## wherein Ar and Ar' represent a halophenyl,alkoxyphenyl, dimethoxyphenyl, hydroxyphenyl, thienyl,trifluoromethylphenyl, or alkylphenyl group, and Alk represents analkylene chain of from 3 to 6 carbon atoms, with anticonvulsant, CNSdepressant and tranquillizing activity.

Belgian patent BE-837878 describes, as intermediates, sometetrahydropyridines of formula ##STR3## wherein Ar is an aryl groupoptionally substituted with one or more groups selected from alkyl,alkoxy, halogen, and CF₃, and R₁ may represent, inter alia, a group##STR4## wherein n is 1, 2, 3, or 4 and X may represent hydrogen orhalogen. French patent FR-1421208 claims tetrahydropyridine derivativesof formula ##STR5## wherein, inter alia, Ar may represent a phenylradical optionally substituted with trifluoromethyl; R₁ and R₂ mayrepresent, inter alia, a bond; X is an alkylene or an alkenylene of 2 or3 carbon atoms; 2 represents a single bond or a group --CH₂ --,--CH(OH)--, --CO--, or --CH(alkyl)-- and R₃ is a m- or p-substituentwhile R₄ and R₅ may represent hydrogen atoms or substituents.

These compounds are described as psychotropes, hypothermic, antiemetic,and general anesthetic potentiating agents.

German patent application DE-A-2904826 describes tetrahydropyridines offormula ##STR6## wherein X is a hydrogen or a chlorine atom and R ishydrogen, alkyl, alkenyl, alkynyl, or phenyl-alkyl, which are endowedwith anorexigenic activity and may also be employed in the treatment ofdepression.

European patent application EP-A-0060176 claims4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridines of formula##STR7## wherein R represents a cyano, acetyl, or cycloalkyl group offrom 3 to 7 carbon atoms, and Alk represents a straight or branchedalkylene of from 1 to 4 carbon atoms, as well as their salts, endowedwith anorexigenic activity.

4-Aryl-1,2,3,6 tetrahydropyridine derivatives of formula ##STR8##wherein Ar may be a phenyl group substituted i.a. with a --CF₃ group andR may represent naphthyl have been described in British patentGB-2083476 as psychotropes.

Anorexigenic trifluoromethylphenyltetrahydropyridine derivatives offormula ##STR9## wherein R represents pyridyl, pyridyl-3-oxide, ornaphthyl, unsubstituted or substituted with a (C₁ -C₄)alkyl group andAlk represents a straight or branched alkylene chain of from 2 to 4carbon atoms have been described in European patent applicationEP-A-0101381. Finally, WO-A-8905779 describes N-alkenyl- orN-alkynyl-tetrahydropyridines of formula ##STR10## wherein R₁, R₂, andR₃ may be hydrogen atoms or alkyl groups, or R₂ and R₃ taken togethermay represent an additional bond and R₄ is a halogen atom, a --CF₃ or analkyl group, which show gastro-intestinal mucous membrane protectingactivity and may therefore be employed for treating or preventinggastric ulcers.

It has now been found that the N-substitutedtrifluoromethylphenyltetrahydropyridines (I) of the present inventionincrease intestinal motility in mammals thus exerting ananti-constipation effect. Some of them have also been tested asantidepressant agents, showing a good antidepressive activity. For thescope of the present invention, the terms "(C₁ -C₄)alkyl" and "(C₁-C₄)alkoxy" include straight or branched alkyl or alkoxy radicalscontaining of from 1 to 4 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, and methoxy, ethoxy, propoxy, isopropoxy, and butoxy,methyl and methoxy being preferred. "Substituted naphthyl" may representa 1-naphthyl or 2-naphthyl radical bearing one or two substituents atpositions 5-, 6-, 7-, and/or 8-.

Salts of the compounds of formula (I) according to the present inventioncomprise both the pharmaceutically acceptable addition salts withmineral or organic acids, such as the hydrochloride, hydrobromide,sulfate, hydrogensulfate, dihydrogenphosphate, citrate, maleate,tartrate, fumarate, gluconate, methansulfonate, 2-naphthalensulfonate,and the like salts, and the acid addition salts with mineral or organicacids which allow an easy separation or crystallisation of the compoundsof formula (I), such as the picrate, oxalate, and the like. A preferredgroup of compounds of the present invention comprises those compounds offormula (I) wherein A is --E--G wherein --E-- is --CH₂ --CH₂ --, whereinone of the hydrogen atoms may be replaced by a methyl group, and --Grepresents naphthyl substituted with one or two hydroxy or methoxygroups, or with two methyl groups. Another preferred group of compoundsof the present invention comprises those compounds of formula (I)wherein A is --L--M wherein --L-- is --Q--CH(OH)-- where --Q-- standsfor --CH₂ -- or --CH(CH₃)-- and --M is as defined above. Particularlypreferred compounds of this last group are those compounds wherein --Mis naphthyl, naphthyl substituted with one or two hydroxy, methoxy ormethyl groups or pyridyl.

A general method for the preparation of the compounds of formula (I) andtheir salts comprises the reaction in an organic solvent of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (II) ##STR11##with a compound of formula (III)

    X--A                                                       (III)

wherein A is as defined above and X represents chloro, bromo, iodo, or agood leaving group such as a methanesulphonate or a p-toluenesulphonate.

As organic solvents, lower alkanols, such as ethanol, n-butanol orn-pentanol, are preferably used, but other solvents such as hexane,dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine, and thelike solvents can also be employed.

The reaction is conveniently carried out in the presence of at least anequimolar amount of a basic condensation agent such as an alkali metalcarbonate or bicarbonate, e.g. sodium or potassium carbonate, or atertiary amine, e.g. triethylamino.

The reaction temperature may vary between room temperature and 200° C.The reaction is generally complete in 4 or 5 hours by heating at80°-150° C., and the thus obtained end product may be isolated accordingto conventional techniques and optionally converted into one of itsaddition salts with a suitably selected organic or inorganic acid.Conversion of the free base into an addition salt thereof is easilyachieved by treating the free base with the selected acid in an inertorganic solvent such as a lower alkanol, e.g. ethanol, or isopropanol,an ether, e.g. dimethoxyethane, or isopropyl ether, an ester, e.g. ethylacetate, or an aliphatic or aromatic hydrocarbon, e.g. hexane, benzene,or toluene.

When a compound of formula (I) is desired wherein A represents a group--E--G or a group --L--M wherein --G, --L--, and --M are as definedabove and --E-- is a group --R--CH₂ -- wherein R is a straight orbranched alkylene chain of from 1 to 3 carbon atoms, an alternativemethod is preferably employed which comprises suitably reducing acompound of formula (IV) ##STR12## wherein --T represents --R--CO--G or--Q--CO--M wherein --R--, --Q--, --G, and --M are as defined above, andif desired, converting the thus obtained products into the correspondingacid addition salts.

When a compound of formula (I) is desired wherein A represents a group--E--G wherein --E-- is a group --R--CH₂ --, reduction of the carbonylgroup to methylene can be carried out according to any of the methodsknown in the chemical literature, such as for instance, the Clemmensenreduction, which involves treating the carbonyl compound of formula (IV)with excess zinc amalgam in a 20 to 40% hydrochloric acid aqueoussolution, optionally in the presence of an organic, water-miecible orimmiscible, solvent, at the reflux temperature of the reaction mixture,or treating it with excess zinc amalgam in an organic solvent containingyazeous hydrogen chloride; the Wolff-Kishner or Huang-Minlon reduction,which involves treating the carbonyl compound of formula (IV) withhydrazone or hydrazone hydrate and decomposing the thus obtainedhydrazone heating it in a high-boiling glycol to 150°-200° C. in thepresence of NaOH or KOH; or even by converting the carbonyl compound offormula (IV) in the corresponding p-toluenesulfonylhydrazone by reactionwith p-toluenesulfonylhydrazine, followed by the reduction of the thusobtained product with NaBH₄ or, better, NaBH₃ CN according to the methoddescribed by R. O. Hutchins et al. in J.Am.Chem.Soc., 1971, 93, p.1793et seq.

If on the contrary, a compound of formula (I) is desired wherein A is agroup L--M, reduction of the carbonyl group to secondary alcohol mayeasily be achieved by well known techniques, by means of an aluminumhydride, such as isobutylaluminum hydride (DIBAL), an aluminum lithiumhydride, such as LiAlH₄, or lithium and trialkoxyaluminum hydrides,boron sodium hydrides, boron zinc hydrides, lithium and trialkylboranehydrides, or analogous hydrides which are suitable to convert a carbonylcompound into a hydroxymethylene group without affecting the otherfunctional groups of the molecule.

The reduction reaction is carried out in an inert organic solvent whichis suitably selected depending on the particular reducing agentemployed. Particularly, when using DIRAL, preferred organic solvents arebenzene, toluene, or 1,2-dimethoxyethane; when using aluminum lithiumhydrides, ethers are preferably employed such as ethyl ether. dioxane,tetrahydrofuran, or 1,2-dimethoxyethane; while, when using NaBH₄, thereaction is preferably carried out in methanol or ethanol. According toa preferred embodiment of the invention, reduction of the carbonyl groupinto hydroxymethylene is carried out with a nearly equimolar amount or aslight excess of a reducing agent with respect to the starting substrateof formula (IV), at a temperature comprised between 0° C. and the refluxtemperature of the solvent employed and more preferably at room or at alower temperature under inert atmosphere.

When reduction of the carbonyl compound of formula (IV) is complete, thecompound (I) wherein A represents a group --E--G or --L--M is recoveredas the free base or its addition salt, --G, --L--, and --M being asdefined above and --E-- representing a group --R--CH₂ --.

The compounds of formula (I) wherein A represents a group --E--G wherein--E-- is a group --CH₂ --R--, wherein --R-- and --G are as definedabove, may also be obtained by reduction of the compounds of formula (V)##STR13## wherein --R-- and --G are as defined above, optionallyfollowed by conversion of the thus obtained product into an acidaddition salt.

In this case reduction of the amide group may easily be achieved byusing an aluminum hydride or a lithium aluminum complex hydride such asLiAlH(OCH₃)₃ or LiAlH₄, in an inert organic solvent such as a linear orcyclic ether e.g. diethyl ether, dioxane, tetrahydrofuran, and1,2-dimethoxyethane, at a temperature of from 0° C. to the refluxtemperature.

According to a preferred embodiment, an equimolar proportion of LiAlH₄with respect to the starting compound of formula (V), is employed andthe reaction is carried out at room temperature and under inertatmosphere using tetrahydrofuran or ethyl ether as the reaction solvent.

The reaction is complete in about 1 hour and affords the compound offormula (I) wherein A represents --E--G wherein --E-- is a --CH₂ --R--group, as the free base or an acid addition salt thereof.

The compounds of formula (I) wherein A is the group --L--M wherein --L--is --Q--CH(OH)-- wherein --Q-- is --CH₂ -- are preferably prepared byreacting the compound of formula (II) with the epoxide (VI) ##STR14##

The condensation reaction between the compound of formula (II) and theepoxide (VI) is typically achieved by heating a mixture of the startingproducts in a lower alkanol such as ethanol, isopropanol, and butanol,optionally in the presence of a basic condensation agent such as analkali metal carbonate.

In a preferred embodiment said condensation reaction is carried out byrefluxing for a few hours a mixture of the compound (II) with at leastthe equimolar amount of the epoxide (VI). When the reaction is complete,the end product is isolated by conventional techniques and if desiredconverted into one of its acid addition salts.

Finally, when by the above processes a compound of formula (I) isobtained wherein A is a group --E--G or --L--M where --G or --Mrepresent naphthyl substituted with one or two methoxy groups, it may betransformed into the corresponding compound wherein --G or --M representnaphthyl substituted with one or two hydroxy groups by demethylation,for instance by treating the methoxylated compound with a concentratedhydrobromic acid solution in water or acetic acid.

Another object of the present invention is therefore a process for thepreparation of a compound of formula (I) ##STR15## wherein A representsa group --E--G or --L--M, where

--E-- is a straight or branched alkylene radical of from 2 to 4 carbonatoms,

--G represents a radical selected from the group consisting of naphthylmono-substituted with hydroxy or (C₁ -C₄)alkoxy; naphthyl di-substitutedwith hydroxy, (C₁ -C₄)alkoxy or (C₁ -C₄)alkyl; or naphthyl substitutedwith methylenedioxy,

--L-- is a --Q--CH(OH)-- group wherein --Q-- is a straight or branchedalkylene radical of from 1 to 3 carbon atoms, and

--M represents a radical selected from the group consisting of naphthyl;naphthyl mono- or di-substituted with hydroxy, (C₁ -C₄)alkoxy or (C₁-C₄)alkyl or naphthyl substituted with methylenedioxy; pyridyl; or (C₁-C₄)alkyl-pyridyl,

or of one of its addition salts with mineral or organic acids, whichcomprises

(a) reacting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (II)##STR16## with a compound of formula (III)

    X--A                                                       (III)

wherein A is as defined above and X represents chloro, bromo, iodo, or agood leaving group; such as a methanesulphonate or ap-toluenesulphonate; or

(b) when a compound of formula (I) is desired wherein A represents agroup --E--G or --L--M wherein --G, --L--, and --M are as defined aboveand --E-- is a group --R--CH₂ -- wherein R is a straight or branchedalkylene chain of from 1 to 3 carbon atoms, reducing a compound offormula (IV) ##STR17## wherein --T stands for --R--CO--G or --O--CO--Mwherein --R--, --Q--, --G, and --M are as defined above; or

(c) when a compound of formula (I) is desired wherein A represents agroup --E--G wherein --E-- is a group --CH₂ --R--, wherein --R-- and --Gare as defined above, reducing the corresponding compound of formula (V)##STR18## wherein --R-- and --G are as defined above; or (d) when acompound of formula (I) is desired wherein A is the group --L--M whereinL-- is --Q--CH(OH)-- where --Q-- is --CH₂ -- and --M is as defined abovereacting 4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine (II)with the epoxide (VI) ##STR19## wherein --M is as defined above; saidprocess being further characterised in that

when a compound of formula (I) is obtained as the free base, it may beconverted into an addition salt thereof,

when a compound of formula (I) is obtained as addition salt, it may beconverted into the corresponding free base or in another addition salt,

when a compound of formula (I) is obtained wherein A represents a group--E--G or --L--M wherein --G or --M represent naphthyl substituted withone or two methoxy groups it may be converted into the correspondingcompound wherein --G or --M represent naphthyl substituted with one ortwo hydroxy groups by demethylation.

The starting compounds of formula (III), when not commerciallyavailable, may be easily prepared by known methods. In particular, thecompounds of formula (III) wherein A represents a group --E--G or --L--Mwherein --E-- is --R--CH₂ -- and --R--, --G, --L--, and --M are asdefined above, may be obtained through Friedel Crafts acylation ofcompounds H--G or H--M respectively wherein --G and --M are as definedabove, with an acid halide of formula (VIIa) or (VIIb) respectively##STR20## wherein --R-- and --Q-- are as defined above and Y is ahalogen atom such as chloro or bromo, in the presence of a Lewis acidunder the conditions which are conventionally employed in this type ofreaction (see G.A. Olah, Friedel-Crafts and related reactions, Volumes1-5, Interscience Publisher, New York, 1963-1967), followed by thereduction of the carbonyl group to methylene or hydroxymethylene.

More particularly, the Friedel-Crafts reaction may be carried out in aninert organic solvent such as carbon sulfide, carbon tetrachloride,methylene chloride, ethylene chloride, nitrobenzene, nitromethane, usingAlCl₃, FeCl₃, SbCl₅, SnCl₄, ZnCl₂, BF₃, TiCl₃, and the like acids as theLewis acids, preferably in equimolar amount or in a slight excess overthe acylating agent. Generally, the catalyst is added to a mixture ofthe two reactants or the substrate HC or HM is added to a mixture of thecatalyst and the acyl halide (VII). The reaction may well proceed atroom temperature but, depending on the substrates and the reactants, aswell as on the reaction solvents and catalysts which are employed it maybetter be carried out either at a lower or higher temperature, typicallyat a temperature comprised between -15° C. and the reflux temperature ofthe reaction mixture, preferably between -10° C. and 40° C. When acompound of formula (III) is desired wherein A is a group --E--G or--L--M wherein --G or --M contain one or two hydroxy substituents,either a Friedel-Crafts catalyst is employed which does not react withthe hydroxy groups, such as ZnCl₂ or BF₃, or the acyl halide (VII) isreacted with compounds HG' or HM' which correspond to the compounds HGor HM respectively wherein the hydroxy groups have been protected as thecorresponding methyl ethers and, at the end of the reaction, said methylgroups are conveniently removed by treatment of the acylated productwith an additional amount of AlCl₃ at high temperatures. Depending onthe optional substitution of the naphthalene or pyridine moieties andthe positions of such optional substituents, the Friedel-Crafts reactionmay afford one or more positional isomers of the compounds of formulaX--R--CO--G or X--Q--CO--M. If a mixture of isomers is obtained, it maybe separated into the single isomers, e.g. by column chromatography,before or after reduction of the carbonyl group. Known techniques may beapplied to the reduction step such as those described above.

The compounds of formula (III) wherein A represents a group --E--Gwherein --E-- stands for --CH₂ --R-- and --R-- and --G are as definedabove, may be prepared by converting the corresponding acid (VIII)##STR21## into the lower alkyl esters thereof, typically the ethylester, reducing the ester group to a primary alcoholic group by a mixedhydride such as LiAlH₄, and replacing the hydroxy group with a group Xby a nucleophilic substitution reaction with an acid H--X wherein Xattacks the positively polarised alcoholic carbon atom.

In their turns, the acids of formula (VIII) may be prepared, dependingon the meaning of --R--, by a number of different methods which arehowever entirely known to any skilled technician. In particular, as anexample, the acids of formula (VIII) wherein --R-- is --CH₂ -- may beprepared by heating a mixture of the compound G--H and bromoacetic orchloroacetic acid in the presence of catalytic amounts of KBr, for a fewhours and isolating the desired product by chromatography.

Alternatively, and preferably, the acids of formula (VIII) wherein --R--represents --CH₂ -- may be prepared through a three-step process whichinvolves as the first step, Friedel-Crafts acylation of the compound offormula G--H with acetyl chloride or bromide in the presence ofcatalytic amounts of a Friedel-Crafts catalyst such as for instanceAlCl₃ or another Lewis acid, followed, in the second step, by conversionof the acetyl group into morpholinylthioacetyl by refluxing for a fewhours a mixture of the acetylated product and a slight molecular excessof sulfur in morpholine, and, in the third step, by treatment of thethus obtained product with sodium hydroxide in ethanol at the refluxtemperature of the reaction mixture and acid hydrolycic of the thusobtained acid (VIII) sodium salt. The thus obtained products may beconverted into the corresponding α-methyl, α-ethyl, α,α-dimethylderivatives (R=CH(CH₃)--, --CH(CH₂ CH₃)--, or --C(CH₃)₂ -- respectively)by alkylation of the carbon atom at the α-position with respect to thecarboxy group, carried out with sodium hydride and the stoichiometricamount of methyl or ethyl iodide in dimethylformamide.

Furthermore, the compounds of formula (VIII) wherein --R-- is --CH₂ --or --CH(CH₃)-- may be converted into the corresponding compounds wherein--R-- represents --CH₂ --CH₂ -- or --CH₂ --CH₂ --CH(CH₃)-- respectively,by the Arndt-Eisteri reaction which involves conversion of the carboxylgroup CH(CH₃)-- respectively, by the Arndt-Eistert reaction whichinvolves conversion of the carboxyl group into acyl chloride bytreatment with thionyl chloride, reaction of said acyl chloride withdiazomethane and conversion of the thus obtained product into thedesired product by treatment with silver oxide (see F. Arndt and B.Eistert, Berichte, 68, 200 (1935)). The compounds of formula (III)wherein A represents a group --E--G wherein --E-- is the group--CH(CH₃)--CH(CH₃)-- may be prepared by treating the compound of formulaG--H with an equimolar amount of an alkyl halide of formulaY--CH(CH₃)--CH(CH₃)--Y wherein Y is as defined above in the presence ofcatalytic amounts of a Lewis acid according to the Friedel-Craftsalkylation reaction and, if a compound of formula (III) is desiredwherein X is different from chloro or bromo, replacing the Y group witha different leaving group.

In some particular cases, alternative processes may be employed for thepreparation of compounds (III), depending on the commercial availabilityof the starting compounds. These alternative processes may be easily setup by any skilled technician on the basis of his chemical knowledge.

The starting compounds of formula (IV) may be prepared by reacting4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (II) with acompound of formula X--R--CO--G (IXa) or X--Q--CO--M (IXb) under thereaction conditions indicated above for the reaction between compounds(II) and (III).

In their turn the compounds of formula (IXa) and (IXb) may be preparedby reacting the compounds of formula H--G and H--M with an ω-haloalkanoic acid of formula Y--R--CO--Y or Y--Q--CO--Y respectivelyaccording to the methodology of the Friedel-Crafts reactions, preferablyat room temperature in methylene or ethylene chloride using AlCl₃ as thereaction catalyst.

At the end of the reaction the desired product is isolated, forinstance, by chromatography, and reacted with the compound of formula(II) to afford the compound (IV).

The compounds of formula (IXa) and (IXb) wherein --R-- and --Q-- are--CH₂ -- and X is chloro or bromo may also be obtained starting from thecorresponding acetylated derivatives of formula CH₃ --CO--G or CH₃--CO--M by treatment with an almost equimolar amount of bromine orchlorine in an inert organic solvent such as chloroform or methylenechloride.

The compounds of formula (V) may be obtained by reacting the4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (II) with afunctional derivative of the acid of formula (VIII) G--R--CO--OH wherein--R-- and --G are as defined above, in an organic solvent at atemperature comprised between -10° C. and the boiling temperature of thesolvent employed.

As suitable functional derivatives, the activated free acid, theanhydride, a mixed anhydride, an active ester, or an acyl balide,preferably the chloride, may be employed. Among the active esters, thep-nitrophenyl ester is particularly preferred, but the methoxyphenyl,trytyl, benzhydryl, and the like esters may also be employed. Thereaction temperature may vary between -10° C. and the boilingtemperature of the solvent employed, but typically the reaction iscarried out at room temperature or at a temperature of from 30° to 50°C. Preferably the reaction is carried out in the cold when it isexothermic, such as for instance when the acyl chloride is employed asthe functional derivative of the acid (VIII).

As for the reaction solvents, preferred are alcohols, such as methanolor ethanol, or halogenated solvents such as methylene chloride,dichloroethane, chloroform, and the like solvents, but other organicsolvents which are compatibles with the reactants employed, such asdioxane, tetrahydrofuran, and hydrocarbons, e.g. hexane, may also beemployed.

The reaction may be carried out in the presence of a proton acceptore.g. an alkali metal carbonate or a tertiary amine, when hydrochloricacid or another acid sets tree during the reaction.

Preferably, the reaction is carried out starting from the free acid inthe presence of benzotriazloyl-N-oxytrisdimethylaminophosphonium hexofluorophosphate (BOP) and of a tertiary aliphatic amine.

Finally, the compounds of formula (VI) may be prepared by cyclisation ofthe corresponding chlorohydrin or bromohydrin by gently heating asolution of the chloro- or bromohydrin in a polar organic solvent suchas an alkanol. In its turn, the chloro- or bromohydrin may simply beobtained in situ, e.g. by reaction of the corresponding ketone withNaBH₄ in an alkanol such as methanol, or ethanol, and directly cyclised.

The starting compounds G-H and M-H are generally known compounds. In anycase they might be prepared by the methods known in the literature fortheir synthesis or for the synthesis of their homologues/analogues withobvious modifications.

The new starting compounds of formula (TV) and (V) wherein --T, --R--,--G, and --M are as defined above, as well as their acid addition saltswith organic or inorganic acids, represent a further specific object ofthe present invention.

It has been found that the compounds of formula (I), as well as theirpharmaceutically acceptable acid addition salts have an intestinalprokinetic activity and may then be employed for the treatment ofintestinal motility disorders and constipation.

To evaluate their anticonstipant activity, representative compounds ofthe present invention have been submitted to a test aimed at evaluatingfecal excretion in rats.

Male rats Crl:CD(SD)BR (Charles River--Italy) weighing 220-250 g areplaced at 8 a.m. in individual grid-floor contention cages. They arefasted during the test session while water is provided ad libitum. At11:30 a.m. the test compounds are administered to the animals eitherorally or subcutaneously in 2 ml of water per kg of body weight. Thetreatment schedule is planned by means of random tables and groups of 8animals each. At the time of drug treatment, rat rectal lumen ismanually emptied from residual feces by gentle pressure and the rats arethen placed again in the same cages. Fecal pellets are then collected 90minutes after s.c. drug treatment or 210 minutes after oral treatment,their number is determined and their wet weight measured. The fecalpellets are then dried in the oven at 40° C. for 10 hours and weighedagain to determine their dry weight. After 5-6 hours, the weight doesnot change any longer, the feces containing approximately the samepercent residual humidity.

The parameter used to evaluate the activity of the test compounds is thedry weight of the feces excreted during 90 minutes (s.c.) or 210 minutes(p.o.) starting from administration of the test compound. Statisticalanalysis of the obtained results uses the Duncan's new multiple analysistest.

The potency of the test compounds is expressed, by means of an activityindex (AI-1 g), as the dose of test compound which induces the excretionof 1 g (dry weight) of feces. Said index is extrapolated from the logdose/activity regression line (p<0.05). Almost no fecal excretion isobserved in the concomitantly tested control animals which received thevehicle only. In the animals treated with high doses of test compounds,a maximum excretion of 12 to 16 fecal pellets with a dry weight of fromabout 1.4 to about 1.6 g, could be attained. With total excretionsexceeding the above values, diarrhoea is clearly, observed and a correctquantification is impossible.

Representative compounds of formula (I) which may be employed for thepreparation of medicaments according to the present invention showed ingeneral an AI-1 g lower than 15 mg/kg p.o. and lower than 5 mg/kg s.c.

Particularly preferred compounds are the compounds of examples 2,6, and7 which, tested as the corresponding hydrochlorides, showed an AI-1 glower than 3 mg/kg p.o.

The compounds of formula (I) may be employed for the preparation ofmedicaments suitable for increasing intestinal motility characterised inthat they contain, as the active principle, one or more compounds offormula (I) or their salts in admixture with a pharmaceutical carrierand optionally with conventional excipients.

The compounds of formula (I) as well as their pharmaceuticallyacceptable salts can be administered orally, rectally, sublingually,transdermally or parenterally. The oral administration route is howeverpreferred and there is no need to utilize different administrationroutes. The amount of active principle which has to be administered forthe treatment of intestinal motility disorders will depend, as usual, onthe particular compound employed, on the nature and severity of theconstipation to be treated, the weight of the patients and theadministration route.

Generally, daily dosages lower than 70 mg, and preferably lower thanabout 40 mg are administered p.o. For parenteral administration thedaily dosage will be comprised between U.1 and 25 mg.

Considering that the administration schedule has to be adapted to thepatient condition, a correct practice comprises beginning the treatmentwith a minimal dose (from 0.1 to 5 mg, preferably from 0.5 to 2.5 mg,the lowest doses being employed for children) administered twice orthree times a day and increasing then the dose or the number ofadministrations until the desired effects are obtained or undesiredside-effects do appear.

The pharmaceutical compositions containing the compounds of formula (I)are prepared according to methods known industrial pharmacy. Inparticular, for the oral administration these medicaments may be in theform of tablets, capsules, elixirs or syrups.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical carrier such asgelatin, starch, lactose, magnesium stearate, talc, arabic gum, and thelike. The tablets may be coated with sucrose or other appropriatematerials or they may be processed so that their dissolution rate isextended or delayed or they continuously release a predetermined amountof active principle.

A preparation in capsules may be easily obtained by mixing the activeingredient with a diluent and by filling the obtained mixture into softor hard gelatin capsules.

A preparation in the form of syrup or elixir or to be administered asdrops, may contain the active ingredient jointly with a sweeteningagent, possibly acaloric, methylparaben and propylparaben asantiseptice, a flavoring agent and a suitable coloring agent, in aliquid vehicle.

Water-dispersible powders or granulates will contain the activeingredient, in admixture with dispersing or wetting agents, or withsuspending agents such as polyvinylpyrrolidone and the like agents, andoptionally with sweetening and/or flavouring agents.

The active principle may also be formulated in the form of microcapsulesor microemulsions optionally with one or more carriers or additives.

For oral administration, each unit dosage form may advantageouslycontain from 0.1 to 50 mg of active principle, preferably from 0.5 to 10mg. In certain cases, however, unit dosage forms containing a higheramount of active principle may as well be envisaged.

For parenteral administration the pharmaceutical compositions accordingto the present invention will contain, in addition to the activeprinciple, one or a mixture of pharmaceutically acceptable, aqueous ornon aqueous, sterile vehicles.

These pharmaceutical compositions may also contain some additives suchas suitable stabilisers, wetting agents, emulsifyers, or dispersants.These compositions for parenteral administration may be sterilised e.g.by filtration through a membrane filter which removes the microorganisms(such as Millipore® filters) or by incorporation of sterilising agentsto the compositions.

These compositions may also be prepared as solid formulations to bedissolved or suspended in sterile water or in another sterile injectablesolvent before use.

For parenteral administration each unit dosage form may advantageouslycontain from 0.05 to 25 mg of active principle and preferably from 0.1to 5 mg.

It has now been further unexpectedly been found that one of thecompounds of the present invention, namely the1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6,7-dimethoxynaphth-2-yl)ethane does exert neurotrophic effects on the nervous system, similar tothose of NGF (Nerve Growth Factor) and increase survival of neurons.

Said effects have been demonstrated by means of an in vitro test on ratsepta as follows.

SOURCE OF BIOLOGICAL MATERIAL

17-18 day old embryos were removed under flow laminary hood from gestantfemale Sprague Dawley rats purchased from Iffa-Credo (France).

Septa were microscopically dissected from embryonic brains in sterileconditions and dissociated with trypsin-EDTA. The resulting cellsuspension was plated in a 1.1 mixture of Dulbecco Modified Eagle (DME)and Ham's F12 media (R. G. Ham, Proc. Nat. Acad. Sci., 1965, 53:288, assold by GIBCO BRL) containing 5% fetal calf serum and 5% horse serum for90 minutes at 37° C. This preplating contributed to the removal ofnon-neuronal cells.

The neuroblasts were then plated at a density of 17×10⁴ cells per cm²either in a minimal serum free medium: DME/Ham's F12 (1:1) with selenium(30 nM) and transferrin (1.25 μM) or in the optimal defined N₂ mediumdescribed by J. E. Bottenstein, G. Sato Eds. (Cell culture in theneurosciences, 3-43, 1985) deprived or not in selenium. The wells werepreviously coated with poly-L-lysine and the cells were maintained at37° C. in an incubator with a humidified 5% CO₂ -95% air atmosphere.

Drug Treatment

Compounds to test were dissolved in dimethyl sulfoxide (DMSO) anddiluted as required in culture medium. The neuroblasts were plated inwells containing the test compound or its respective solvent, andmaintained for 4 days without changing the medium.

Experimental Procedure

After 4 days in culture, the medium was removed and replaced with atetrazolium salt[3-bromo-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] dissolvedin culture medium (0.15 mg/ml). The cells were incubated for 4 hours at37° C. The mitochondrial succinodehydrogenases of living cells reducethe tetrazolium salt to formazan blue, which after solution in DMSO isread at the optical density of 540 nm which is linearly correlated withthe number of living cells (Manthorpe et al., Dev. Brain Res., 1988, 25:191-198).

Statistical Analysis

The results were expressed as mean±SEM of the optical density obtainedin the different groups (8 to 20 wells per group) The analysis of thestatistical difference between the experimental and correspondingcontrol groups was performed using the two-tailed Dunnet "t" test.

In this test, the1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6,7-dimethoxynaphth-2-yl)ethane,affording survival of neuronal cells in a very poor medium, free fromgrowth factors, this compound being more effective than those describedin U.S. Pat. No. 5,270,320.

In the light of the results obtained in the above model, the use of thiscompound as well as of its pharmaceutically acceptable salts in thetreatment and/or prevention of diseases involving neuronal degenerationcan be envisaged.

A further object of the present invention is a method of treating orpreventing neuronal degenerative processes which comprises administeringto a mammal in need thereof the1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6,7-dimethoxynaphth-2-yl)ethaneor a pharmaceutically acceptable salt thereof.

More particularly the present invention concerns a method for treatingor preventing memory impairments, vascular dementia, post-encephaliticdisorders, post-apoplectic disorders, post-traumatic syndrome caused bybrain injury, cerebral anoxic diseases, Alzheimer's disease, seniledementia, subcortical dementia such as Huntington's chorea andParkinson's disease, AIDS dementia, neuropathies provoked by sympatheticor sensory nerve necrosis or lesions, cerebral oedema or spinocerebellardegenerations, which comprises administering to a mammal in need thereofthe1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6,7-dimethoxynaphth-2yl)ethaneor a pharmaceutically acceptable salt thereof.

The following examples further illustrate the invention without howeverlimiting it.

Preparation I 6,7-dimethoxy-2-naphthylacetic acid

(a) A mixture of 6,7-dimethoxy-2-acetylnaphthalene (6 g, 0.026 mol),sulfur (1 g, 0.03 mol), morpholine (5.5 ml) and a catalytic amount ofp-toluenensulfonic acid is heated to the reflux temperature for 4 hours.The mixture is then cooled and ethanol (20 ml) is added thereto. Afterstanding at room temperature overnight, the precipitate is recovered byfiltration and crystallised from benzene (100 ml) affording4-[(6,7-dimethoxy-naphth-2-yl)thioacetyl]morpholine (4.8 g). M.p.158°-161° C.

(b) A mixture of the thus obtained product (4.7 g, 0.014 mol), NaOH (2.3g, 0.057 mol), ethanol (50 ml) and water (23 ml) is heated to the refluxtemperature for 4 hours, then the mixture is concentrated to dryness andthe residue is dissolved in water. The aqueous solution is washed withethyl ether, concentrated hydrochloric acid is added thereto up to pHabout 1 and the desired product is allowed to crystallise (2.3 g). M.p.134°-136° C.

Preparation II (6,7-dimethoxy-naphth-2-yl)oxirane

(a) A solution of bromine (4.5 g, 0.029 mol) in chloroform (30 ml) isadded dropwise to a solution of 6,7-dimethoxy-2-acetylnaphthalene (6.7g, 0.029 mol) in a mixture chloroform (70 ml)/methanol (15 ml). Once thereaction mixture discoloures, it is concentrated to dryness and theresidue is treated with a mixture ethyl ether/isopropyl ether. The thusobtained solid is triturated with methanol yielding6,7-dimethoxy-2-(2-bromoacetyl)naphthalene (6 g). M.p. 120°-122° C.

(b) NaBH₄ (1.6 g) is added portionwise to a suspension of the aboveproduct (6 g, 0.019 mol) in methanol (80 ml). The temperature of thereaction mixture rises to 40° C. The obtained solution is stirred for 1hour and then concentrated to dryness. The obtained residue is dissolvedin ethyl acetate, the organic solution is washed with water, dried andconcentrated to dryness. A residue is thus obtained which is trituratedwith isopropyl ether yielding the compound of the title (2.6 g). M.p.115°-117° C.

EXAMPLE 11-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6-methoxy-naphth-2-yl)propanehydrochloride

(a) A solution of 6-methoxy-α-methyl-2-naphthylacetic acid (3.5 g, 0.015mol), triethylamine (4.3 ml, 0.03 mol),4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride(3.9 g, 0.015 mol), andbenzotriazolyl-N-oxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) (6 g, 0.015 mol) in methylene chloride (40 ml) is stirred at roomtemperature for 4 hours. Ethyl acetate (150 ml) is then added theretoand the mixture is washed in sequence with water, 10% NaHCO₃, water, 1NHCl, and water. The reaction mixture is then filtered over silica andconcentrated to dryness affording1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6-methoxy-naphth-2-yl)propane(4 g) as a thick oil.

(b) A solution of the thus obtained product in tetrahydrofuran (40 ml)is added dropwise to a suspension of LiAlH₄ (0.7 g, 0.018 mol) intetrahydrofuran (10 ml) and the reaction mixture is stirred for 3 hours.Water (1.5 ml) is dropwise added thereto and stirring is prolonged foradditional 2 hours. Then the mixture is filtered, the filtrate isconcentrated to dryness and the thus obtained residue is dissolved inethyl acetate (80 ml). The solution is filtered over silica and thefiltrate is concentrated to dryness. The residue is dissolved in acetoneand hydrogen chloride is added thereto. The hydrochloride whichprecipitates is recovered by filtration and crystallised from acetone(40 ml), affording1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6-methoxy-naphth-2-yl)propanehydrochloride (1.5 g). M.p. 182°-184° C.

EXAMPLE 22-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-(naphth-2-yl)ethanolhydrochloride

A mixture of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (2.7g, 0.01 mol), potassium carbonate (2.7 g, 0.02 mol), and2-naphthyl-oxirane (2.7 g, 0.015 mol) in butanol (50 ml) is heated tothe reflux temperature for 2 hours. The mixture is then concentrated todryness, the residue is dissolved in ethyl acetate, the obtainedsolution is washed with water, dried and concentrated to dryness. Theresidue is triturated with ethyl ether, filtered and dissolved in hotisopropanol. Concentrated hydrochloric acid is added thereto and thehydrochloride is allowed to crystallise, thus affording the compound ofthe title (1.9 g). M.p. 245°-247° C.

EXAMPLE 31-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6-methoxy-naphth-2-yl)ethanehydrochloride

(a) A solution of 6-methoxy-2-naphthylacetic acid (1.8 g, 0.009 mol),4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride(2.4 g, 0.009 mol), triethylamine (2.4 ml, 0.018 mol), and BOP (3.7 g,0.009 mol) in methylene chloride (40 ml) is stirred at room temperaturefor 5 hours. Then it is concentrated to dryness, the obtained residue isdissolved in a mixture ethyl ether/water, the organic phase isseparated, and washed sequentially with 1N HCl, water, 5% NaOH, andwater. The reaction mixture is then filtered over silica and thefiltrate is concentrated to dryness affording1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6-methoxy-naphth-2-yl)ethane(3.1 g). M.p. 102°-105° C.

(b) A solution of the thus obtained product (3 g, 0.007 mol) intetrahydrofuran (30 ml) is added dropwise to a suspension of LiAlH₄ (0.5g, 0.013 mol) in ethyl ether (30 ml) and the reaction mixture is stirredat room temperature for 3 hours. Water (1.2 ml) is added thereto andstirring is prolonged, still at room temperature, for additional 2hours. Then the mixture is filtered, the filtrate is concentrated todryness and the thus obtained residue is dissolved in ethyl acetate. Thesolution is washed with water and dried. Then HCl saturated isopropanolis added thereto and the hydrochloride which precipitates is recoveredby filtration and crystallised from 95% ethanol (150 ml) yielding thecompound indicated in the title (2 g). M.p. 260°-263° C.

EXAMPLE 41-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6-hydroxy-naphth-2-yl)ethanehydrobromide

A mixture of1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6-methoxy-naphth-2-yl)ethanehydrochloride (0.6 g, 0.0013 mol) (obtained as described in Example 3)and 33% HBr in acetic acid (20 ml) is refluxed for 4 hours. Theprecipitate which forms is recovered by filtration and crystallised from95% ethanol affording the compound indicated in the title (0.3 g) withm.p. 210°-212° C.

EXAMPLE 51-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6,7-dimethyl-naphth-2-yl)ethanehydrochloride

(a) A solution of 6,7-dimethyl-2-naphthylacetic acid (1 g, 0.0046 mol),4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloridechloride (1.2 g, 0.0046 mol), triethylamine (1.3 ml, 0.009 mol), and BOP(1.8 g, 0.0046 mol) in methylene chloride (30 ml) is stirred at roomtemperature for 4 hours. The mixture is then concentrated to dryness,the residue is dissolved in ethyl ether, the organic solution is washedsequentially with water, 1N NaOH, water, 1N HCl, and water. The reactionmixture is then filtered over silica and the filtrate is concentrated todryness thus affording1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6,7-dimethyl-naphth-2-yl)ethane(0.6 g).

(b) A suspension of the thus obtained product (0.6 g, 0.0014 mol) andLiAlH₄ (0.25 g, 0.006 mol) in ethyl ether (10 ml) and tetrahydrofuran(10 ml) is stirred at room temperature for 3 hours. Water (0.7 ml) isadded thereto and stirring is prolonged, still at room temperature, foradditional 2 hours. Then the mixture is filtered, the filtrate isconcentrated to dryness and the thus obtained residue is dissolved inhot isopropanol. The solution is acidified with HCl in ethanol andallowed to crystallise thus affording the compound indicated in thetitle (0.2 g), M. p. 245°-247° C.

EXAMPLE 61-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6,7-dimethoxy-naphth-2-yl)ethanehydrochloride

(a) A mixture of 6,7-dimethoxy-2-naphthylacetic acid (2.3 g, 0.0093mol), 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride (2.4 g, 0.009 mol), triethylamine (2.5 ml, 0.018 mol), andBOP (3.8 g, 0.009 mol) in methylene chloride (50 ml) is stirred at roomtemperature for 4 hours. The mixture is then concentrated to dryness,the residue is dissolved in a mixture ethyl ether/water, the organicphase is separated and washed sequentially with 1N HCl, water, 1N NaOH,and water. The reaction mixture is then dried and concentrated todryness. The obtained residue is purified by chromatography eluting witha mixture ethyl ether/ethyl acetate 1/1, thus affording1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6,7-dimethoxy-naphth-2-yl)ethane(2.6 g).

(b) A solution of the thus obtained product (2.6 g, 0.0057 mol) in ethylether (40 ml) is added dropwise to a suspension of LiAlH₄ (0.5 g, 0.013mol) in ethyl ether (20 ml) and the thus obtained reaction mixture isstirred at room temperature for 4 hours. Excess LiAlH₄ is destroyed bythe cautious addition of water (1.2 ml). The reaction mixture is allowedto stand overnight and filtered. The filtrate is washed with 1N NaOH andthen with water, the organic phase is dried and concentrated to dryness.The obtained residue is dissolved in isopropanol, the organic solutionis made acidic by the addition of HCl and allowed to crystallise thusaffording the compound of the title (1.5 g) which is recrystallised fromethanol, M.p. 215°-217° C.

EXAMPLE 71-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-hydroxy-2-(6-dimethoxy-naphth-2-yl)ethanehydrochloride

A solution of (6,7-dimethoxynaphth-2-yl)oxirane (2.5 g, 0.014 mol),4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (3.1 g, 0.013mol) in ethanol (50 ml) is refluxed for 4 hours. The mixture is allowedto stand overnight and then it is filtered. The thus recovered productis dissolved in boiling ethanol (20 ml) and 37% HCl (2 ml), and allowedto crystallise therefrom thus affording the compound of the title (1.5g). M.p. 232°-234° C.

EXAMPLE 81-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-hydroxy-2-(pyrid-2-yl)ethanehydrochloride

A mixture of 2-pyridyl-oxirane (1.21 g, 0.01 mol)(JAC3, 1976, 98(7),1952), and 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (2.4g, 0.01 mol) in absolute ethanol (45 ml) is refluxed for 4 hours. Themixture is then concentrated to dryness and the residue is purified bysilica gel column chromatography eluting with a mixture ethylacetate/methanol 9/1. The fractions which contain the desired productare pooled together, and evaporated to dryness. The residue is taken upin acetone, and hydrogen chloride saturated isopropanol is addedthereto. The precipitate is recovered and crystallised from isopropanol(140 ml) thus affording the compound of the title (1.5 g). M.p.192°-196° C.

We claim:
 1. A method of treating neuronal degenerative processes whichcomprises administering to a mammal in need thereof, the1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-2-(6,7-dimethoxynaphth-2-yl)ethane or a pharmaceutically acceptable salt thereof,wherein said compound is administered in an amount effective to treatsaid neuronal degeneration.
 2. The method of claim 1 for the treatmentof memory impairments, vascular dementia, post-encephalitic disorders,post-apoplectic disorders, post-traumatic syndrome caused by braininjury, cerebral anoxic diseases, Alzheimer's disease, senile dementia,subcortical dementia such as Huntington's chorea and Parkinson'sdisease, AIDS dementia, neuropathies provoked by sympathetic or sensorynerve necrosis or lesions, cerebral oedema or spinocerebellardegenerations.
 3. The method of claim 2 for the treatment of vasculardementia, senile dementia and Alzheimer's disease.